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Review
. 2022 Aug;298(8):102117.
doi: 10.1016/j.jbc.2022.102117. Epub 2022 Jun 9.

Coming full circle: On the origin and evolution of the looping model for enhancer-promoter communication

Tessa M Popay  1 , Jesse R Dixon  2
Affiliations
Review

Coming full circle: On the origin and evolution of the looping model for enhancer-promoter communication

Tessa M Popay et al. J Biol Chem. 2022 Aug.

Abstract

In mammalian organisms, enhancers can regulate transcription from great genomic distances. How enhancers affect distal gene expression has been a major question in the field of gene regulation. One model to explain how enhancers communicate with their target promoters, the chromatin looping model, posits that enhancers and promoters come in close spatial proximity to mediate communication. Chromatin looping has been broadly accepted as a means for enhancer-promoter communication, driven by accumulating in vitro and in vivo evidence. The genome is now known to be folded into a complex 3D arrangement, created and maintained in part by the interplay of the Cohesin complex and the DNA-binding protein CTCF. In the last few years, however, doubt over the relationship between looping and transcriptional activation has emerged, driven by studies finding that only a modest number of genes are perturbed with acute degradation of looping machinery components. In parallel, newer models describing distal enhancer action have also come to prominence. In this article, we explore the emergence and development of the looping model as a means for enhancer-promoter communication and review the contrasting evidence between historical gene-specific and current global data for the role of chromatin looping in transcriptional regulation. We also discuss evidence for alternative models to chromatin looping and their support in the literature. We suggest that, while there is abundant evidence for chromatin looping as a major mechanism for enhancer function, enhancer-promoter communication is likely mediated by more than one mechanism in an enhancer- and context-dependent manner.

Keywords: 3D genome; CTCF; Cohesin; TAD; chromatin structure; genome structure; promoter; transcription; transcription enhancer.

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Conflict of interest statement

Conflict of interest The authors declare that they have no conflicts of interest with the contents of this article.

Figures

Figure 1
Figure 1
Mechanisms to enable enhancer-promoter communication.A, a tethering protein supports close spatial proximity of the enhancer and promoter, with the intervening chromatin maintained in a loop structure. B, in the sliding model, a protein initially associates with the enhancer before translocating along DNA to the promoter. C, to link an enhancer with its promoter, protein binding to the enhancer may initiate formation of a protein bridge to transmit signals to the promoter. D, changes in chromatin conformation are propagated from the enhancer to the promoter, leading to alterations in the local promoter structure.
Figure 2
Figure 2
TheCohesin complex as the mediator of the loop extrusion process.A, the ring-like Cohesin complex (green) is loaded onto chromatin through the activity of NIPBL/MAU2, with Cohesin subsequently translocating outward, bringing the enhancer and promoter into close spatial proximity. B, components of the Cohesin complex. The core complex members are RAD21, SMC3, SMC1, and one of the mutually exclusive STAG proteins. NIPBL and MAU2 are primarily thought to contribute to loading Cohesin onto DNA. C, Cohesin depends on a number of proteins to enable its function on chromatin. The primary known factors responsible for Cohesin function are NIPBL/MAU2 for Cohesin loading, WAPL for Cohesin removal, and CTCF for blocking Cohesin translocation and stabilizing it on chromatin.
Figure 3
Figure 3
Scenarios enablingCohesin-dependent andCohesin-independent transcriptional regulation.A, E-P loops remain intact following removal of Cohesin, due to either limited diffusion or an additional tethering factor maintaining the loop structure. B, transcriptional activation requires only initial E-P looping, such as that required to transfer transcriptional machinery from the enhancer to promoter. When Cohesin is absent, the loop structure is lost, but the constitutive transcription is retained. C, for a subset of genes, Cohesin and loop formation are necessary prerequisites for transcriptional activation. This could mean that Cohesin promotes loop formation in response to an activating signal or that loop formation enables the activating signal to be transmitted. E-P, enhancer–promoter.
Figure 4
Figure 4
Non-looping models of enhancer function.A, enhancers could play a tethering role to control the distribution of chromatin in the nucleus. For example, regions of chromatin that are tethered to the nuclear lamina by an enhancer may experience transcriptional repression, whereas regions tethered to nuclear speckles are more likely to be activated. Similarly, enhancers may drive the clustering of chromatin into transcription factories, which are environments that are rich in transcriptional regulators and favor transcriptional activation. B, phase separation is largely thought to be driven by the formation of large protein clusters. Due to the number of protein-binding sites present in enhancers and promoters, these regions tend to accumulate protein and this may lead to condensate formation, essentially bringing enhancers and promoters into close spatial proximity.
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